Drugs that have abuse liability in humans typically serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals and serve as discriminative stimuli controlling two-lever choice behavior. Experiments are being conducted to assess neuropharmacological and behavioral mechanisms underlying drug self-administration behavior and behavior controlled by drugs as discriminative stimuli in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. We have demonstrated persistent intravenous self-administration behavior by experimentally and drug-naive squirrel monkeys for doses of THC comparable to those in marijuana smoke inhaled by humans (Justinova et al. 2003). The ability of THC to maintain drug-taking behavior in monkeys without a history of exposure to other drugs shows that this drug possesses reinforcing properties of its own that are not dependent on prior self-administration of other drugs (such as cocaine; see Tanda et al. 2000). Thus, self-administration of THC by squirrel monkeys provides a reliable animal model of human marijuana abuse, suitable for studying the relative abuse liability of other natural and synthetic cannabinoids and for developing new therapeutic strategies for the treatment or prevention of marijuana abuse in humans. There is increasing experimental evidence from animal studies for reciprocal functional interactions between endogenous brain cannabinoid and opioid systems. Most of the evidence for a role of opioid systems in the modulation of the reinforcing effects of THC or cannabinoids is indirect and comes from behavioral studies in rodents. We tested the hypothesis that the opioid system may play a role in the addictive properties of cannabinoids in non-human primates (Justinova et al. 2004). We used naltrexone, an opioid antagonist clinically used for the treatment of opiate abuse or alcoholism. Pretreatment with naltrexone in squirrel monkeys self-administering THC resulted in a significant reduction of the self-administration behavior maintained by THC. In contrast, naltrexone pretreatment had no significant effect on cocaine self-administration responding under identical conditions. This experiment indicates that blockade of opioid receptors can modulate the addictive effects of THC in non-human primates, and it is in agreement with other preclinical studies showing that blockade of opioid receptors modulates the behavioral and neurochemical effects of cannabinoids. Also, we have recently reported that the cannabinoid CB1 receptor antagonist SR141716A reduces, but does not completely block, the reinforcing effects of heroin using fixed-ratio and progressive-ratio schedules of intravenous heroin injection in rats, further suggesting that opioid-cannabinoid interactions can be bi-directional (Solinas et al. 2003). Although cannabis possesses addictive properties, there is a continuing debate on the possibility of legalizing cannabis use for medical purposes and decriminalizing its recreational use. One of the arguments used against legalization is so called ?gateway drug? hypothesis which says that cannabis use could increase the probability of encountering, trying and eventually becoming addicted to other illicit drugs such as heroin. In a recent study (Solinas et al. 2004), we investigated the effects of pre-exposure to THC on subsequent intravenous self-administration of heroin by Sprague-Dawley rats. We used a level of exposure previously shown to produce behavioral sensitization to THC and cross-sensitization to morphine. Rats were exposed to escalating doses of THC twice a day for three days (2, 4 and 8 mg/kg i.p. on successive days). In one group of rats, we studied 1) acquisition of heroin self-administration behavior using a continuous-reinforcement [fixed-ratio (FR) 1] schedule, 2) heroin dose-response relationships using an FR1/variable-dosse schedule, and 3) reinforcing efficacy of heroin using a progressive-ratio schedule. Rats pre-exposed to THC subsequently self-administered significantly more heroin injections per session and showed significantly shorter post-injection pauses over a range of heroin doses (12.5-100 ?g/kg/injection) using the variable-dose schedule. Interestingly, the maximum effort rats would exert to receive an injection of the different doses of heroin under the progressive-ratio schedule was not altered by THC pre-exposure. Altogether, our results demonstrate that pre-exposure to THC alters some pharmacological effects of heroin that determine frequency of heroin-taking, but offers no support for the hypothesis that pre-exposure to THC alters heroin?s efficacy as a reinforcer. In another study, we have evaluated the effects of histamine H3 antagonists in rats on methamphetamine self-administration and discrimination performance and on methamphetamine-induced dopamine release in the shell of the nucleus accumbens. The main finding was that histamine H3 receptor antagonists can potentiate both the reinforcing and discriminative actions of methamphetamine and that this is associated with a potentiation by the histamine H3 antagonists of methamphetamine-induced dopamine release in the shell of the nucleus accumbens (Munzar et al. 2004). Both thioperamide and clobenpropit dose-dependently increased self-administration of a low 0.03 mg/kg injection dose of methamphetamine and reduced self-administration of a higher dose of 0.06 mg/kg/injection of methamphetamine. Also, neither thioperamide nor clobenpropit reinstated drug-seeking behavior when given during saline extinction and neither produced any change in extracellular levels of dopamine in the shell of the nucleus accumbens when given alone. Both H3 antagonists, however, markedly enhanced methamphetamine-induced dopamine release. Although underlying neurochemical mechanisms for observed interactions of histamine H3 receptors with the behavioral and neurochemical actions of methamphetamine remain speculative, the present findings point to histamine H3 receptors as a new and promising target for development of medications for the treatment of psychostimulant abuse. We previously reported that rats which actively self-administered methamphetamine for 5 weeks showed downregulation of dopamine D2 autoreceptors in the midbrain and this was not seen in rats that passively received injections of methamphetamine or saline at the same time (yoked controls). Since sigma-1 receptors (Sig-1R) are implicated in behavioral sensitization, conditioned place preference, and cellular restructuring induced by psychostimulants, we have now examined neuroadaptive changes in Sig-1R in the brains of rats self-administering methamphetamine. As in previous studies, two groups of rats served as yoked controls and passively received an injection of either methamphetamine or saline each time a response-contingent injection of methamphetamine was actively self-administered by a third group of rats. After 5 weeks brains were dissected and protein and mRNA levels of Sig-1R were then measured by Western and Northern blottings, respectively. There was a marked upregulation of Sig-1R proteins (50%) in the midbrain and altered levels of Sig-1R mRNA in the frontal cortex and hippocampus of rats that learned to actively self-administer methamphetamine, but not in yoked methamphetamine- or saline-control rats. These neuroadaptive changes in Sig-1R may be related to the downregulation of D2 autoreceptors we previously observed and may contribute to the reinforcing effects of methamphetamine, either by potentiating the physiological and subjective effects of methamphetamine directly or by facilitating development of learned associations between the effects of methamphetamine injections, environmental stimuli, and operant nose-poking responses leading to injections.